Down-Syndrome-Induced Senescence Disrupts the Nuclear Architecture of Neural Progenitors

Authors

• Hiruy S Meharena
• Asaf Marco
• Vishnu Dileep
• Elana R Lockshin
• Grace Y Akatsu
• James Mullahoo
• L Ashley Watson
• Tak Ko
• Lindsey N Guerin
• Fatema Abdurrob
• Shruthi Rengarajan
• Malvina Papanastasiou
• Jacob D Jaffe
• Li-Huei Tsai

Language

English

Publication Date

1-6-2022

Journal

Cell Stem Cell

DOI

10.1016/j.stem.2021.12.002

PMID

34995493

PMCID

PMC8805993

PubMedCentral® Posted Date

1-6-2023

PubMedCentral® Full Text Version

Author MSS

Abstract

Down syndrome (DS) is a genetic disorder driven by the triplication of chromosome 21 (T21) that is characterized by a wide-range of neurodevelopmental and physical disabilities. Transcriptomic analysis of tissue samples from individuals with DS has revealed that T21 induces a genome-wide transcriptional disruption. However, the consequences of T21 on the nuclear-architecture and its interplay with the transcriptome remain unknown. In this study, we find that unlike human induced pluripotent stem cells (iPSCs), iPSC-derived neural progenitor cells (NPCs) exhibit genome-wide “chromosomal introversion”, disruption of lamina-associated domains, and global chromatin-accessibility changes in response to T21, consistent with the transcriptional and nuclear-architecture changes characteristic of senescent cells. Treatment of T21-harboring NPCs with senolytic drugs alleviates the transcriptional, molecular and cellular dysfunctions associated with DS. Our findings provide a mechanistic link between T21 and global transcriptional disruption, and indicate that senescence-associated phenotypes may play a key role in the neurodevelopmental pathogenesis of DS.

Keywords

Down Syndrome, Gene Expression Profiling, Humans, Induced Pluripotent Stem Cells, Neural Stem Cells, Transcriptome, Down syndrome, Aneuploidy, 3D-Genome, Epigenome, Transcriptome, Lamina-associated domains (LADs), Senescence, Senolytics, Neurodevelopment, Cell-Proliferation, Cell-Migration, Hi-C, ATAC-seq, RNA-seq, ChIP-seq

Published Open-Access

yes

Recommended Citation

Meharena, Hiruy S; Marco, Asaf; Dileep, Vishnu; et al., "Down-Syndrome-Induced Senescence Disrupts the Nuclear Architecture of Neural Progenitors" (2022). Faculty, Staff and Students Publications. 8557.
https://digitalcommons.library.tmc.edu/baylor_docs/8557